ABSTRACT Curing HIV/AIDS requires strategies to purge reservoirs harboring latent, transcriptionally silent proviruses, as HIV persists in CD4+ T memory cells even in the presence of effective highly active antiretroviral therapy. Despite intensive research, our understanding of the molecular mechanisms that seed and maintain the HIV reservoir in primary human CD4+ memory T cells remains incomplete. Our preliminary data indicate that interleukin-15 (IL-15), the only gamma cytokine up-regulated during acute HIV infection, increases human CD4+ T memory cell susceptibility to infection by inactivation of the restriction factor SAMHD1. Further, IL-15 specifically increases the number of CD4+ T memory cells with stem cell like properties (TSCM) in HIV-infected CD4+ T cell populations. We hypothesize that HIV infected CD4+ T memory cells with stem cell-like properties (CD4+ T central memory/stem cell-like) initiate and maintain the persistent viral reservoir in patients with controlled viral replication. We will probe the molecular mechanisms controlling infection susceptibility and latency maintenance in primary human CD4+ T cells using established techniques, such as mass-cytometry by time of Flight (CyTOF), genome editing and next generation sequencing. We will identify abortive, silent and productive infections in CD4+ T memory cells, define the cellular programs specific for HIV persistence and modulate these pathways to render CD4+ T memory cells refractory to infection. We will examine how FDA approved JAK1/2 and mTOR inhibitors modulate infection and proliferation of CD4+ T memory cells. We will define cell lineages responsible for HIV persistence in vivo by generating hierarchical maps of patient-derived proviruses inserted at the same genetic location but obtained from distinct CD4+ T memory populations using high-resolution, next generation sequencing approaches. The proposed studies will not only characterize the CD4+ T memory cells that establish and maintain the HIV reservoir, but also examine whether FDA approved therapeutic interventions may be used to prevent latent HIV infection and/or eliminate HIV persistence in the human CD4+ T memory cell compartment.